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Tumor targeted delivery of immunomodulators by nanopolymers

a technology of immunomodulator and nano-polymer, which is applied in the direction of peptides, drug compositions, peptides, etc., can solve the problems of reducing the anti-tumor activity of metastatic melanoma, exhausting the pool of this important type of anti-tumor cells outside, etc., to achieve enhanced anti-tumor activity, reduce or even abolish the systemic activation of pdc, and enhance the retention of tumor sites

Inactive Publication Date: 2012-12-06
BOARD OF RGT THE UNIV OF TEXAS SYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]Targeted delivery of CpG to melanoma in vivo through biodegradable L-PG is presented herein where this delivery system effectively generates the protective immunity required and enhances antitumor activity and reduces or even abolishes the systemic activation of pDC. Biodegradable polymers conjugated to tumor binding ligands and antibodies which can target tumors with enhanced retention in tumor sites are described. By way of example, one such polymer conjugate is poly(L-glutamic acid)-CpG conjugate (“L-PG-CpG”). L-PG-CpG has been shown to reduce tumor growth better than free CpG, and triggers a stronger systemic CD8 T response toward tumor antigen (OVA). This macrophage-tropic polymer interacts with tumor infiltrating macrophages and accumulates in tumor sites.

Problems solved by technology

Conventional therapies currently have limited efficacy against metastatic melanoma.
Unfortunately, systemic injection of CpG causes activation of pDC cells in major immune organs, and exhausts the pool of this important type of anti-tumor cells outside of the tumor.

Method used

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  • Tumor targeted delivery of immunomodulators by nanopolymers
  • Tumor targeted delivery of immunomodulators by nanopolymers
  • Tumor targeted delivery of immunomodulators by nanopolymers

Examples

Experimental program
Comparison scheme
Effect test

##ic example 1

Prophetic Example 1

To Determine the Optimal Physicochemical Characteristics of PG-CpG to their Anticancer Effect Following Intratumoral Injection

[0079]Following intratumoral injection, PG-based CpG nanoconstructs with optimal physicochemical properties activate pDC locally, without inducing systemic immune response, leading to potent immunotherapeutic effect.

Rationale and Overall Strategy.

[0080]In preliminary studies above, we have shown significantly enhanced antitumor activity of intratumorally injected L-PG-CpG compared to intratumorally injected free CpG. However, the mechanisms that enhance the immunopotency of CpG and mediate strong antitumor effect of PG-CpG are not fully understood. Several factors may contribute to this activity, including (i) a depot effect whereby L-PG-CpG is retained in the tumor for a prolonged period of time and CpG is slowly released from the site of its injection; (ii) enhanced delivery of CpG to APC and DC in the tumor; (iii) co-delivery of L-PG-CpG...

##ic example iii

Prophetic Example III

The Effect of L-PG-CpG Nanoconstructs Used Alone and in Combination with T Regulatory Cell Depletion on Antitumor Immunity

[0122]The combination of intratumoral injection of nano-CpG (best from Example I) or intravenous injection of targeted nano-CpG (best from Example II) and therapies targeting costimulatory pathways will lead to robust antitumor activity through activation of multiple innate and adaptive immune cells. Additionally, these treatment plans can further incorporate the use of such cytokines as IL-2 and IFN-α, which have shown some promise in the clinical area, but still have room for improvement.

Rational and Overall Strategy

[0123]It is generally accepted that effective immunotherapy of cancer depend on acting on multiple checkpoints of the immune stimulation. Combined use of immunotherapeutic agents that synergize through different mechanisms has been a critical area of research. Full activation of immunity requires stimulation of positive costimul...

##ic example iv

Prophetic Example IV

In Vivo Analysis

[0137]Female mice (about 600 per year) of C57BL / 6 inbred strain and GFP-transgenic mice will be used for these experiments.

[0138]The major procedures to be performed with mice include the following:[0139]Since in vivo tumor elimination and in vivo immune responses are keys to understanding the anticancer efficacy of the nanocarrier-CpG candidates being developed, the proposed studies can only be tested in animals. For statistical significance of the data generated, we will repeat the assay at least once and use 10 mice per test per group.[0140]The animals will be maintained in a pathogen-free holding facility for small animal, at the M. D. Anderson where alternating 12-h periods of light and darkness, temperature, and humidity are controlled as approved by the American Association for the Accreditation of Laboratory Animal Care (AAALAC). All procedures will be performed by trained staff and approved by the Institutional Animal Care and Use Committ...

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Abstract

Nanoconstructs having three components: (1) biodegradable nanopolymers and nanoparticles, (2) immunodrugs such as CpG, and a (3) tumor binding device, which are actively targeted to tumor cells such as melanoma cells through receptor-mediated uptake and methods of using the same are described. Antitumor immunity is further enhanced by combination of PG-CpG nanoconstructs with agonists of positive costimulatory signals and inhibitors of negative immune regulatory signals.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 301,252 filed on Feb. 4, 2009. The application is incorporated by reference herein in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]None.THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT[0003]None.REFERENCE TO SEQUENCE LISTING[0004]None.FIELD OF THE INVENTION[0005]Nanoconstructs comprising biodegradable polymers conjugated to tumor binding ligands and antibodies which can target tumors with enhanced retention in tumor sites are described. Antitumor immunity is further enhanced by combination of the nanoconstructs with agonists of positive costimulatory signals and inhibitors of negative immune regulatory signals.BACKGROUND OF THE INVENTION[0006]Melanoma is the deadliest of the skin cancers due to its propensity to widely metastasize throughout the body. Once it has spread to distal sites, the median survival is less than 6...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/02A61P35/00C07K14/00
CPCA61K47/48238A61K47/4833A61K47/48315A61K47/62A61K47/645A61K47/646A61P35/00
Inventor ZHOU, DAPENGLI, CHUNHWU, PATRICK
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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